Mesothelioma

Mesothelioma is a form of cancer that is almost always caused by exposure to asbestos. In this disease, malignant cells develop in the mesothelium, a protective lining that covers most of the body’s internal organs. Its most common site is the pleura (outer lining of the lungs and internal chest wall), but it may also occur in the peritoneum (the lining of the abdominal cavity), the heart, the pericardium (a sac that surrounds the heart) or tunica vaginalis.

Most people who develop mesothelioma have worked on jobs where they inhaled asbestos particles, or they have been exposed to asbestos dust and fiber in other ways. It has also been suggested that washing the clothes of a family member who worked with asbestos can put a person at risk for developing mesothelioma. Unlike lung cancer, there is no association between mesothelioma and smoking, but smoking greatly increases the risk of other asbestos-induced cancers.

Despite treatment with chemotherapy, radiation therapy or sometimes surgery, the disease carries a poor prognosis. Research about screening tests for the early detection of mesothelioma is ongoing.

Contents

Signs and Symptoms

Symptoms of mesothelioma may not appear until 20 to 50 years after exposure to asbestos. Shortness of breath, cough, and pain in the chest due to an accumulation of fluid in the pleural space are often symptoms of pleural mesothelioma.

Symptoms of peritoneal mesothelioma include weight loss and cachexia, abdominal swelling and pain due to ascites (a buildup of fluid in the abdominal cavity). Other symptoms of Peritoneal Mesothelioma may include bowel obstruction, blood clotting abnormalities, anemia, and fever. If the cancer has spread beyond the mesothelium to other parts of the body, symptoms may include pain, trouble swallowing, or swelling of the neck or face.

These symptoms may be caused by mesothelioma or by other, less serious conditions.

Mesothelioma that affects the pleura can cause these signs and symptoms:

Chest wall pain

Pleural effusion, or fluid surrounding the lung

Shortness of breath

Fatigue or anemia

Wheezing, hoarseness, or cough

Blood in the sputum (fluid) coughed up (hemoptysis)

In severe cases, the person may have many tumor masses. The individual may develop a pneumothorax, or collapse of the lung. The disease may metastasize, or spread, to other parts of the body.

Tumors that affect the abdominal cavity often do not cause symptoms until they are at a late stage. Symptoms include:

Abdominal pain

Ascites, or an abnormal buildup of fluid in the abdomen

A mass in the abdomen

Problems with bowel function

Weight loss

In severe cases of the disease, the following signs and symptoms may be present:

Causes

Mesothelioma is caused by asbestos exposure which occurs when fibers are inhaled or ingested into the body and become lodged in body cavities, causing inflammation or infection. Asbestos is a naturally-occurring fibrous substance that was widely used in the 20th century in a number of different industries. When the public became aware of the hazards associated with the mineral, warnings were issued in the mid-1970s and use of the product began to decline.

Diagnosis

If the signs and symptoms that indicate mesothelioma are present, the doctor will conduct a physical exam to check for any lumps or other unusual signs. The doctor may order imaging scans, such as a chest X-ray or a computerized tomography (CT) scan of the chest or abdomen, to look for abnormalities.

It’s not uncommon for mesothelioma to be misdiagnosed initially because mesothelioma is rare, and its signs and symptoms aren’t specific. The doctor will likely rule out other more common conditions before considering mesothelioma.

Biopsy

Biopsy, a procedure to remove a small portion of tissue for laboratory examination, is the only way to determine whether a patient has mesothelioma. Depending on what area of the body is affected, the doctor selects the right biopsy procedure for the patient. Options include:

Fine-needle aspiration. The doctor removes fluid or a piece of tissue with a small needle inserted into the chest or abdomen.

Thoracoscopy. Thoracoscopy allows the surgeon to see inside the chest. In this procedure, the surgeon makes one or more small incisions between the ribs. A tube with a tiny video camera is then inserted into the chest cavity — a procedure sometimes called video-assisted thoracoscopic surgery (VATS). Special surgical tools allow the surgeon to cut away tissue for testing.

Laparoscopy. Laparoscopy allows the surgeon to see inside the abdomen. Using one or more small incisions into the abdomen, the surgeon inserts a tiny camera and special surgical tools to obtain a small piece of tissue for examination.

Thoracotomy. Thoracotomy is a surgery to open the chest between the ribs to allow a surgeon to check for signs of disease. He or she removes a sample of tissue for testing.

Laparotomy. Laparotomy is surgery to open the abdomen to allow a surgeon to check for signs of disease. He or she removes a sample of tissue for testing.

The tissue sample is analyzed under a microscope to see whether the abnormal tissue is mesothelioma and what types of cells are involved. The type of mesothelioma determines the treatment plan.

Staging

Once mesothelioma is diagnosed, the doctor orders other tests to determine the extent, or stage, of the cancer. Imaging tests that may help determine the stage of the cancer include:

Chest X-ray

CT scans of the chest and abdomen

Magnetic resonance imaging (MRI)

Positron emission tomography (PET)

Once the extent of pleural mesothelioma is determined, a stage is assigned. Formal stages aren’t available for other types of mesothelioma because these types are rare and aren’t well studied. The stages of pleural mesothelioma are:

I. Stage I – pleural mesothelioma is considered localized cancer, meaning it’s limited to one portion of the lining of the chest.

II. Stage II – mesothelioma may have spread beyond the lining of the chest to the diaphragm or to a lung.

III. Stage III – mesothelioma may have spread to other structures within the chest and may involve nearby lymph nodes.

IV. Stage IV – mesothelioma is an advanced cancer that has spread to distant areas (metastasized).

Pathogenesis/Pathophysiology

The mesothelium consists of a single layer of flattened cuboidal cells forming the epithelial lining of the serous cavities of the body including the peritoneal, pericardial and pleural cavities. Deposition of asbestos fibers in the parenchyma of the lung may result in the penetration of the visceral pleura from where the fiber can then be carried to the pleural surface, thus leading to the development of malignant mesothelial plaques. The processes leading to the development of peritoneal mesothelioma remain unresolved, although it has been proposed that asbestos fibers from the lung are transported to the abdomen and associated organs via the lymphatic system. Additionally, asbestos fibers may be deposited in the gut after ingestion of sputum contaminated with asbestos fibers.

Pleural contamination with asbestos or other mineral fibers has been shown to cause cancer. Long thin asbestos fibers (blue asbestos, amphibole fibers) are more potent carcinogens than “feathery fibers” (chrysotile or white asbestos fibers). However, there is now evidence that smaller particles may be more dangerous than the larger fibers. They remain suspended in the air where they can be inhaled, and may penetrate more easily and deeper into the lungs.

Mesothelioma development in rats has been demonstrated following intra-pleural inoculation of phosphorylated chrysotile fibers. It has been suggested that in humans, transport of fibers to the pleura is critical to the pathogenesis of mesothelioma. This is supported by the observed recruitment of significant numbers of macrophages and other cells of the immune system to localized lesions of accumulated asbestos fibers in the pleural and peritoneal cavities of rats. These lesions continued to attract and accumulate macrophages as the disease progressed, and cellular changes within the lesion culminated in a morphologically malignant tumor.

Experimental evidence suggests that asbestos acts as a complete carcinogen with the development of mesothelioma occurring in sequential stages of initiation and promotion. The molecular mechanisms underlying the malignant transformation of normal mesothelial cells by asbestos fibers remain unclear despite the demonstration of its oncogenic capabilities. However, complete in vitro transformation of normal human mesothelial cells to malignant phenotype following exposure to asbestos fibers has not yet been achieved. In general, asbestos fibers are thought to act through direct physical interactions with the cells of the mesothelium in conjunction with indirect effects following interaction with inflammatory cells such as macrophages.

Analysis of the interactions between asbestos fibers and DNA has shown that phagocytosed fibers are able to make contact with chromosomes, often adhering to the chromatin fibers or becoming entangled within the chromosome. This contact between the asbestos fiber and the chromosomes or structural proteins of the spindle apparatus can induce complex abnormalities. The most common abnormality is monosomy of chromosome 22. Other frequent abnormalities include structural rearrangement of 1p, 3p, 9p and 6q chromosome arms.

Common gene abnormalities in mesothelioma cell lines include deletion of the tumor suppressor genes:

Neurofibromatosis type 2 at 22q12

P16INK4A

P14ARF

Asbestos has also been shown to mediate the entry of foreign DNA into target cells. Incorporation of this foreign DNA may lead to mutations and oncogenesis by several possible mechanisms:

Asbestos fibers have been shown to alter the function and secretory properties of macrophages, ultimately creating conditions which favor the development of mesothelioma. Following asbestos phagocytosis, macrophages generate increased amounts of hydroxyl radicals, which are normal by-products of cellular anaerobic metabolism. However, these free radicals are also known as clastogenic and membrane-active agents thought to promote asbestos carcinogenicity. These oxidants can participate in the oncogenic process by directly and indirectly interacting with DNA, modifying membrane-associated cellular events, including oncogene activation and perturbation of cellular antioxidant defenses.

Asbestos also may possess immunosuppressive properties. For example, chrysotile fibres have been shown to depress the in vitro proliferation of phytohemagglutinin-stimulated peripheral blood lymphocytes, suppress natural killer cell lysis and significantly reduce lymphokine-activated killer cell viability and recovery. Furthermore, genetic alterations in asbestos-activated macrophages may result in the release of potent mesothelial cell mitogens such as platelet-derived growth factor (PDGF) and transforming growth factor-β (TGF-β) which in turn, may induce the chronic stimulation and proliferation of mesothelial cells after injury by asbestos fibers.

Prevention

Treatment

Treatment of malignant mesothelioma using conventional therapies in combination with radiation and or chemotherapy on stage I or II Mesothelioma have proved an average of 74.6 percent success rate in extending the patient’s life span by five years or more (this percentage may increase or decrease depending on date of discovery / stage of malignant development – Oncology Today, 2009). Treatment course is primarily determined by the staging or development. This is unlike traditional treatment such as surgery by itself, which has proved only by 16.3 percent likely to extend a patient’s life span by five years or more. Clinical behavior of the malignancy is affected by several factors including the continuous mesothelial surface of the pleural cavity which favors local metastasis via exfoliated cells, invasion to underlying tissue and other organs within the pleural cavity, and the extremely long latency period between asbestos exposure and development of the disease.

Surgery

Surgery, by itself, has proved disappointing. However, research indicates varied success when used in combination with radiation and chemotherapy (Duke, 2008) A pleurectomy/decortication is the most common surgery, in which the lining of the chest is removed. Less common is an extrapleural pneumonectomy (EPP), in which the lung, lining of the inside of the chest, the hemi-diaphragm and the pericardium are removed.

Radiation

For patients with localized disease, and who can tolerate a radical surgery, radiation is often given post-operatively as a consolidative treatment. The entire hemi-thorax is treated with radiation therapy, often given simultaneously with chemotherapy. This approach of using surgery followed by radiation with chemotherapy has been pioneered by the thoracic oncology team at Brigham & Women’s Hospital in Boston. Delivering radiation and chemotherapy after a radical surgery has led to extended life expectancy in selected patient populations with some patients surviving more than 5 years. As part of a curative approach to mesothelioma, radiotherapy is also commonly applied to the sites of chest drain insertion, in order to prevent growth of the tumor along the track in the chest wall.

Although mesothelioma is generally resistant to curative treatment with radiotherapy alone, palliative treatment regimens are sometimes used to relieve symptoms arising from tumor growth, such as obstruction of a major blood vessel. Radiation therapy when given alone with curative intent has never been shown to improve survival from mesothelioma. The necessary radiation dose to treat mesothelioma that has not been surgically removed would be very toxic.

Chemotherapy

Chemotherapy is the only treatment for mesothelioma that has been proven to improve survival in randomized and controlled trials. The landmark study published in 2003 by Vogelzang and colleagues compared cisplatin chemotherapy alone with a combination of cisplatin and pemetrexed (brand name “Alimta” chemotherapy) in patients who had not received chemotherapy for malignant pleural mesothelioma previously and were not candidates for more aggressive “curative” surgery. This trial was the first to report a survival advantage from chemotherapy in malignant pleural mesothelioma, showing a statistically significant improvement in median survival from 10 months in the patients treated with cisplatin alone to 13.3 months in the combination pemetrexed group in patients who received supplementation with folate and vitamin B12. Vitamin supplementation was given to most patients in the trial and pemetrexed related side effects were significantly less in patients receiving pemetrexed when they also received daily oral folate 500mcg and intramuscular vitamin B12 1000mcg every 9 weeks compared with patients receiving pemetrexed without vitamin supplementation. The objective response rate increased from 20% in the cisplatin group to 46% in the combination pemetrexed group. Some side effects such as nausea and vomiting, stomatitis, and diarrhea were more common in the combination pemetrexed group but only affected a minority of patients and overall the combination of pemetrexed and cisplatin was well tolerated when patients received vitamin supplementation; both quality of life and lung function tests improved in the combination pemetrexed group. In February 2004, the United States Food and Drug Administration approved pemetrexed for treatment of malignant pleural mesothelioma. However, there are still unanswered questions about the optimal use of chemotherapy, including when to start treatment, and the optimal number of cycles to give.

Cisplatin in combination with raltitrexed has shown an improvement in survival similar to that reported for pemetrexed in combination with cisplatin, but raltitrexed is no longer commercially available for this indication. For patients unable to tolerate pemetrexed, cisplatin in combination with gemcitabine or vinorelbine is an alternative, or vinorelbine on its own, although a survival benefit has not been shown for these drugs. For patients in whom cisplatin cannot be used, carboplatin can be substituted, but non-randomized data have shown lower response rates and high rates of hematological toxicity for carboplatin-based combinations, albeit with similar survival figures to patients receiving cisplatin.

In January 2009, the United States FDA approved using conventional therapies such as surgery in combination with radiation and or chemotherapy on stage I or II Mesothelioma, after a research conducted by a nationwide study of Duke University concluded an almost 50 point increase in remission rates.

Immunotherapy

Treatment regimens involving immunotherapy have yielded variable results. For example, intrapleural inoculation of Bacillus Calmette-Guérin (BCG) in an attempt to boost the immune response, was found to be of no benefit to the patient (while it may benefit patients with bladder cancer). Mesothelioma cells proved susceptible to in vitro lysis by LAK cells following activation by interleukin-2 (IL-2), but patients undergoing this particular therapy experienced major side effects. Indeed, this trial was suspended in view of the unacceptably high levels of IL-2 toxicity and the severity of side effects such as fever and cachexia. Nonetheless, other trials involving interferon alpha have proved more encouraging with 20% of patients experiencing a greater than 50% reduction in tumor mass combined with minimal side effects.

Heated Intraoperative Intraperitoneal Chemotherapy

A procedure known as heated intraoperative intraperitoneal chemotherapy was developed by Paul Sugarbaker at the Washington Cancer Institute. The surgeon removes as much of the tumor as possible followed by the direct administration of a chemotherapy agent, heated to between 40 and 48°C, in the abdomen. The fluid is perfused for 60 to 120 minutes and then drained.

This technique permits the administration of high concentrations of selected drugs into the abdominal and pelvic surfaces. Heating the chemotherapy treatment increases the penetration of the drugs into tissues. Also, heating itself damages the malignant cells more than the normal cells.